1. Field of Invention
The present invention relates generally to an apparatus and a method of producing particles, and particularly to a method of using an apparatus to produce freeze-dried particles.
2. Description of Related Art
Molecules of protein, peptide and other biological compounds require special consideration and handling during formulation and processing as a therapeutic or pharmaceutical. For example, contact with alcohols can denature some proteins and peptides. In addition, temperature extremes (hot or cold) can damage some proteins and peptides and reduce or eliminate biological activity.
Preparing protein therapeutics as dry powders is usually required to overcome stability problems with liquid formulations. A common process for making dry solid formulations of a biomaterial is freeze-drying, also known as lyophilization. This technique does not directly produce particles in the narrow micro- or nano-meter size range. Conventional lyophilization techniques are known to have uneconomically long process cycles (primary and secondary drying stages) and high energy cost. Further, inherent limitations of the conventional lyophilization include uneven moisture distribution, inconsistent stability, and unpredictable properties of the final product. Micro- or nano-meter size particles are preferred in various delivery systems and therefore further processing of the particles is required, for example, micronization is a process that reduces particle size. However, mechanical micronization can be time-consuming and inefficient for soft and ductile organic pharmaceuticals. Further, mechanical micronization can have an adverse effect on dry-powder formulation so as to render the formulation partially or completely ineffective.
The drying time for a typical freeze-drying or lyophilization is undesirable long because it is performed in several steps: primary drying to remove the loose solvent and secondary drying to remove solvent bonded to the solute. A cake with small, thin capillaries is usually produced during the primary drying process. The capillaries are the means by which the vapor travels to the surface and is removed. Thus, the smaller the capillary, the longer the time necessary for drying. Also, the capillaries are subject to collapse at elevated temperatures. So, the process is performed slowly at undesirably low temperatures (e.g. below −20° C.). Therefore, current lyophilization techniques are uneconomical in terms of cost and time. Much of the cost can be ascribed to the length of the time required for the primary drying step, which can require several days to complete. It would be economically advantageous to increase sublimation rates and shorten primary drying times during lyophilization.
A spray-drying process or technique is used to produce pharmaceutically active particles. For example, the spray drying technique is useful to achieve the goal of producing dry powders of therapeutic proteins (such as insulin) for pulmonary delivery. An advantage of the spray-drying process is the direct production of particles that are porous or hollow. Spray drying reduces the need for micronization as a size-reducing processing step. In a particular spray-drying process, a sprayed drug solution or emulsion is used that includes an excipient. The excipient can serve as a blowing agent, and can stabilize the active compound during formulation. Spray-drying is particularly suitable for use with proteins and peptides that are labile or damaged by mechanical micronization. In addition, spray-drying is suitable for use with drugs having a narrow therapeutic index, and which require a very high fine particle fraction (FPF). A reduction of inter-particle interactions results in a corresponding increase of the FPF (in excess of 50%).
The excipient can produce porous or hollow structures in particles formed using the excipient. Porous particles are particularly suited for aerosol drug delivery because of their low particle density (about 0.1 g/cm3). The low particle density results in a mass-median aerodynamic diameter (MMAD) that is smaller than the volume diameter by a factor of about three.
Unfortunately, conventional spray-drying is not a universal technique. The inlet temperature during operation is increased to remove a solvent; the temperature can exceed 100° C., and may be as high as 220° C. for aqueous solutions. The higher temperatures associated with conventional spray-drying can contribute to chemical and/or physical instability with reference to the active ingredient and/or the formulation excipient. Thus, thermally labile materials are precluded from use with the conventional spray-drying technique.
The disadvantageous elevated temperatures of spray-drying have been addressed in the art by various methods. One such method is spray freeze-drying, which involves the use of a solution containing a protein and an excipient. A solution is sprayed into a low-temperature liquid, for example, liquid nitrogen. The frozen droplets are then freeze-dried using a standard lyophilization procedure. Such processes are disclosed in U.S. Pat. No. 6,284,282, which is hereby incorporated by reference in its entirety.
Unfortunately, the low temperature of the low-temperature liquid, and the corresponding abrupt decrease of temperature during the spraying, can degrade some proteins, peptides and other biologically active materials. This can be especially problematic for a process that sprays small particles having a large specific surface area. A relatively long contact time of liquid droplets with dispersing gas can cause aggregation of protein molecules into a form that is inactive or has a reduced activity.
The drying of spray freeze-dried products is also performed in several steps similar to conventional lyophilization techniques described hereinabove. The drying time for spray freeze-drying is undesirable long and is performed at undesirably low temperatures. The abrupt temperature drop produces particles or a cake with small, thin capillaries. The capillaries are the means by which the liquid travels to the surface and is removed. Thus, the smaller the capillary, the longer the time necessary for drying. Also, the capillaries are subject to collapse at elevated temperatures. So, to ensure that the capillaries remain open, the process is performed at very low temperatures (below −40° C.). The droplet/air interface during the spraying stage may lead to protein de-activation or aggregation. Further, liquid nitrogen is difficult to handle on a large scale, and the process requires a liquid nitrogen receiving tank and/or multiple nozzles delivering freezing (liquid) nitrogen and dispersing (gaseous) nitrogen. The use of the liquid nitrogen is necessary in the conventional process to increase the consistency of freeze-drying process.
Vacuum-assisted freezing is another process for the preparation of small particles of temperature-sensitive compounds. In vacuum-assisted freezing, a solution is introduced into an evacuated chamber in the form of a spray. Droplets of the spray are at a sufficiently low temperature to freeze at the vacuum pressure inside the chamber. The frozen solvent is sublimated from the collected frozen droplets. Such a procedure is disclosed in U.S. Pat. No. 5,727,333, which is hereby incorporated by reference in its entirety. Unfortunately, the use of vacuum limits the solution throughput, and thus hinders industrial scale-up. A further disadvantage of the vacuum-assisted freezing technique is that the process temperature must be maintained in a very narrow temperature range for consistent freezing of droplets from cooled solutions. And, biologically active molecules can be damaged at the gas-liquid interface so that the biological activity is reduced.
Methods involving supercritical fluid (SCF) precipitation facilitate particle formation at near-ambient temperatures, and eliminate a need for a liquid-vapor interface. However, SCF precipitation has disadvantages because water and carbon dioxide (CO2) are poorly miscible fluids, and therefore any precipitation technique using CO2 and an aqueous solution requires the addition of an organic co-solvent to increase the solubility of water in CO2. Unfortunately, the organic co-solvent is likely to be a protein denaturant. Many biologically active materials are irreversible degraded as a result of contacting the organic co-solvent. Loss of biological activity is also pronounced when the denaturing effect of organic solvent is exacerbated by an increased processing temperature.
Carbon dioxide-assisted nebulization with bubble-drying (CAN-BD) is a processing technique using a supercritical fluid. A CAN-BD process is disclosed in U.S. Pat. No. 5,639,441, which is hereby incorporated by reference in its entirety. The solubility of supercritical or compressed CO2 in water or organic solvents is used in CAN-BD to generate small droplets or bubbles, and hot air or nitrogen is used to evaporate the solvent and form solid particles. The CAN-BD method is relatively simple, and allows for the processing of water-soluble compounds without use of organic solvents. CAN-BD claims the use of a reduced processing temperature relative to conventional spray-drying processing temperatures. Unfortunately, the CAN-BD processing temperature, of about 65° C. is still high enough to damage some proteins with or without co-formulation with an excipient. As in conventional spray-drying processes, there is a large droplet/vapor interface which may lead to protein aggregation or de-activation. In addition, it is problematic for the CAN-BD method to produce desirable porous or hollow particles. Generally, the production yield of small particles is low due to difficulties in collecting and retaining such small particles. The solvent content of particles produced is typically higher than the solvent content of particles produced by lyophilization. A high residual solvent content can create problems for long-term stability of some biological molecules. Further, CAN-BD has the disadvantage of an increased gas-liquid interfacial area, which potentially leads to aggregation and deactivation of proteins.
Aerogel processing has produced particles having a relatively high porosity and surface area. An example of aerogel processing is disclosed in the WIPO publication WO 02/051389, which is hereby incorporated by reference in its entirety. The aerogels are produced from modified organic carrier matrices. The matrices are saturated with a therapeutic agent, dried with supercritical CO2 and micronized using a jet-mill. Measured aerogel densities are as low as 0.003 g/cm3.
The particles produced by aerogel processing have a relatively large volume diameter, and therefore may show reduced interparticle interactions and better aerosolization relative to high-density (>1 g/cm3) solid particles. A disadvantage aerogel processing is the complexity and extensive use of organic solvents and reaction chemicals. The organic solvents and reaction chemicals can degrade a biologically active material or make the formulation otherwise unacceptable. Further, aerogel processing is not suitable for such common regulatory-accepted excipients as pure lactose, and may be problematic for industrial scale-up.
It would be desirable to have a particle formation method to produce particles of water-soluble compounds, such as thermo-labile therapeutic proteins or other biomaterials, with or without an excipient. It would further be desirable to have a particle formation method that produces uniform particles at desirable temperatures so as not to reduce the biologically activity of selected molecules. It also would be desirable to increase the consistency and to reduce the production cost of powders compared to standard lyophilization or spray-freeze drying techniques. And, it would be desirable to have a controllable method for producing particles suitable for aerosol formulations in a reduced time frame that is economical and desirable, and preferably at a relatively decreased capital cost for processing equipment.